The overall objective of this project is to devise and test various modes and combinations of antibody-mediated chemotherapy of cancer. The experimental model to be used is the xenografted GW-39 human colonic carcinoma system, from which we have isolated a number of tumor-associated antigens, such as carcinoembryonic antigen (CEA) and colon-specific antigen-p (CSAp) (1,2). Specific antibodies to these colonic, tumor associated markers will be produced and covalently conjugated to a number of antitumor drugs, such as Daunomycin, Chlorambucil, and Methotrexate. Studies will be undertaken to determine the correct dose of either antibody or drug applied separately, as single or as multiple doses, and then as a conjugate. The activity of the antibody and the drugs used will be assessed after covalent binding, prior to in vivo therapy experiments. In addition to assessing the possible improved therapeutic efficacy of the antibody-drug conjugate as compared to either component used alone, the antitumor effects of the drug and antibody administered as a mixture will also be determined. Antitumor activity in vivo will be assessed by measuring the change in growth of GW-39 tumors growing in hamsters, as well as the survival time of these tumor-bearing animals. In addition to using goat IgG antibodies to CEA and CSAp, antibody fragments lacking the Fc portion will be used. Later studies will focus on the possible advantage of hybridoma-derived monoclonal IgG antibodies and IgG fragments to CEA and CSAp. Combinations of CEA- and CSAp-antibody-mediated therapy regimens will also be studied. This could involve varying the drugs conjugated to the different antibodies. This project is consistent with the objectives of the Biological Response Modifiers Program.